The association of specific alleles and haplotypes at the HLA class I and class II loci with a variety of autoimmune diseases is well established. Recently, polymorphisms in the Killer Immunoglobulin-like Receptors (KIR) genes that encode the stimulatory and inhibitory receptors on NK cells have been reported to be associated with a few of the same HLA-associated diseases, (eg psoriatic arthritis, scleroderma, and T1D). The ligands recognized by many of these receptors are epitopes on HLA class I molecules. Our goal is to carry out case/control association analyses for Crohn's Disease and Rheumatoid Arthritis using our high resolution HLA and KIR genotyping methods. We have developed high throughput, robust, and high resolution immobilized probe methods for genotyping the HLA class I and class II loci and a high throughput MALDI-TOF method for genotyping the KIR loci. Specific DRB1 alleles have already been associated with each of these diseases (DRB1*0103 for CD and DRB1*0401 and *0404for RA) but we will evaluate the role of other HLA loci in these diseases. HLA class I typing is also critical in evaluating the role of the KIR genes since the association data must be stratified on the presence or absence of the HLA epitope ligand to examine the effects of KIR-HLA combinations. In addition, we will genotype another well established disease gene polymorphism, the PTNP22 locus, allowing stratification of the HLA and KIR association data. The analyses of HLA-KIR in population-based studies will add significantly to our understanding of the role of the innate immune system in these complex autoimmune disorders.